This Project will extend ongoing recent work in our laboratory where we established the region of the nucleus accumbens as an important substrate for the reinforcing properties of heroin in non-physically dependent rats self-administering heroin intravenously. The present proposal will continue these studies by exploring further the central mechanisms involved in opiate reinforcement and will extend these studies to exploring the central mechanisms involved in opiate dependence. The experiments proposed are designed to examine the role of the nucleus accumbens and its efferent projections in opiate reinforcement in non dependent animals, and to compare these results with similar studies in physically dependent animals. At the same time the neuronal sites of action important for precipitated opiate withdrawal will be explored in dependent animals by using local intracerebral injections of methylnaloxonium, a selective opiate antagonist with greatly reduced lipophilicity and diffusability. Withdrawal measures will include both unconditioned and conditioned behavior. Significant evidence exists to show that rats, monkeys and man show behavioral and physiological manifestation of narcotic withdrawal as a response to previously neutral stimuli that have been paired with a state of precipitated abstinence. An attempt will be made to define the functional substrate for the phenomenon of conditioned narcotic withdrawal by attempting to reverse conditioned withdrawal with local intracerebral injection of morphine or opioid peptides. These studies have important implications for our understanding of the neural substrates involved in opiate seeking behavior and the addictive process.